There are approximately 9 million alcoholics in the United States. A great majority of these will experience injury to endocrine tissues as a consequence of alcohol abuse. Such injury will be manifest by gonadal atrophy with combined endocrine and reproductive failure, hypothalamic-pituitary injury manifested by inadequate secretion of pituitary hormones under basal conditions or in response to releasing factor stimulation, and in some cases hypersecretion of cortisol as manifested by the pseudoCushing's syndrome. Moreover, chronic alcoholic men particularly those with liver disease frequently are feminized. Studies performed in large part by the principal investigator have provided a partial basis for these phenomena. It has been shown that alcohol is both a testicular toxin and an ovarian toxin. It has been shown that alcoholics and normal volunteers fed alcohol acutely have abnormal pituitary responses to both luteinizing hormone releasing factor (LRF) and thyrotropin releasing factor (TRH). Finally it has been shown that some alcoholic men are feminized and that such feminization is associated with the presence of low plasma levels of androgen and increased levels of estrogen. The increase in estrogens have been shown also to occur as a consequence of increased peripheral nonhepatic aromatization of weak adrenal androgens principally estrone. During the proposed grant period, it is planned to pursue these problems further. Specifically 1) the effects of alcohol and acetaldehyde on the endocrine functioning of the testes and of the adrenal glands of rats will be evaluated in an in vitro organ perfusion system; and 2) the effect of portal hypertension associated with the development of advanced alcoholic induced liver disease will be evaluated on sex hormone plasma levels, their plasma clearance, biliary excretion and interconversions.